Combination therapy with cabozantinib and cannabidiol enhances the apoptotic cell death via phosphorylation of TP53 regulated by ER-stress in hepatocellular carcinoma

Abstract Cannabidiol (CBD), a primary constituent of hemp and cannabis, has pharmacologically broad properties for a variety of diseases including cancer. Cabozantinib (CBZ), a potent multikinase inhibitor, has been approved for use in patients with advanced hepatocellular carcinoma (HCC). Recently, research is increasing for combination therapy using CBZ for better improved efficacy and safety for the patients. Here, we investigated the effect of the combination therapy with CBZ and CBD in HCC cells. CBD enhances the sensitivity of CBZ against HCC cells by increasing cytotoxicity and apoptosis. Especially, analysis of phospho-kinase array demonstrated that the apoptotic effect of combination treatment with CBZ and CBD was significantly related phosphorylation of TP53 regulated by endoplasmic reticulum stress (ER-stress) compared to other kinases. Inhibition of TP53 expression and ER-stress abolished the apoptotic effect of combination treatment with CBZ and CBD, revealing no expression changes in Bax, Bcl-2, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9. On the other hand, we found that the effect of combination treatment with CBZ and CBD was not associated with cannabinoid receptor 1 (CNR1) and CNR2 receptors signaling pathway. Our findings suggest that combination therapy with CBZ and CBD provides enhanced therapeutic efficacy against HCC. Citation Format: Youngsic Jeon, Taejung Kim, Hyukjoon Kwon, Jungyeob Ham, Young-Joo Kim. Combination therapy with cabozantinib and cannabidiol enhances the apoptotic cell death via phosphorylation ofTP53 regulated by ER-stress in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2678.